Research – University of Copenhagen

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Research

Background

Infections due to multidrug-resistant (MDR) bacteria are rapidly increasing worldwide. In particular, clinical isolates of carbapenem-resistant Gram-negative bacteria (Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, Acinetobacter spp.) are challenging as they are only sensitive to last-resort antibiotics (e.g. colistin and/or tigecycline). Recent emergence and global distribution of transferrable colistin resistance (mcr-1, -2) render the risk for pan-resistant infections a likely scenario in the near future. This problem is aggravated by a drug discovery pipeline containing few novel classes of antibiotics against these pathogens. Thus development of antimicrobial agents with targets and mode of action different from current antibiotics is urgently needed.

Although antimicrobial peptides (AMPs) are crucial in Nature’s fight against bacteria, and have been studied intensively by academia for many years, the industry has until very recently essentially discarded them as potential antibiotics since their properties comply poorly with standard screening in the industry and due to challenging pharmacokinetics and in vivo toxicity. Nevertheless, we are convinced that by an innovative scientific approach, adapted to the special features of peptides as well as the critical drug properties required for clinical approval, peptide-based compounds will be prominent amongst future drugs against MDR bacteria.

Research objectives

Across biology AMPs constitute a central part of innate immune systems, and most intriguingly both last-resort antibiotics and more recently discovered leads are peptide-based. Thus, AMPs and mimics thereof have reappeared as attractive sources of novel antibiotics, not least due to their alternative mode of action, structural diversity, and potential for rapid optimization.

The research objectives are to:

i) Discover narrow-spectrum antisense PNA (peptide nucleic acid) antibiotics targeting resistance, virulence or essential bacterial gene expression

ii)  Identify and characterize novel antibiotic targets using innovative biological expression methodologies and advanced molecular biology tools

iii) Develop membrane-permeabilizing peptidomimetics as adjunct antibiotics, capable of potentiating efficacy of clinically approved antibiotics on resistant clinical isolates

iv) Discover bacteria-penetrating peptides that can act as bacterial delivery agents

v) Elucidate the molecular mechanisms responsible for membrane permeabilization and transport across the bacterial envelope.

vi) Investigate the pharmacodynamics and pharmacokinetics of AMPs, antibacterial peptidomimetics and peptide nucleic acid (PNA) antibiotics in vivo.